tbuckley/cabot-search huggingface dataset:
Abstract 3702: UBE4B interacts with the ITCH E3 ubiquitin ligase to induce Ku70 and c-FLIPL K63/K48 branched polyubiquitination and enhanced neuroblastoma HDACi-mediated apoptosis
Authors: Christophe Le Clorennec, Divya Subramonian, Yuchen Huo, Peter E. Zage
Journal: Cancer Research (2022)

Abstract Expression of the UBE4B ubiquitin ligase is associated with neuroblastoma patient outcomes, but the functional roles of UBE4B in neuroblastoma pathogenesis are not known. We evaluated interactions of UBE4B with the E3 ubiquitin ligase ITCH/AIP4 and the effects of UBE4B expression on Ku70, c-FLIPL, and p53 ubiquitination and proteasomal degradation by co-immunoprecipitation and Western blots. We also evaluated the role of UBE4B in apoptosis induced by HDAC inhibition in our neuroblastoma cell lines model using Western blots. UBE4B was found in a complex with ITCH, with binding mediated by WW domains in the ITCH protein. ITCH activation led to ITCH-UBE4B E3-E4 ubiquitin ligase complex formation and recruitment of Ku70 and c-FLIPL via ITCH WW domains, followed by Ku70 and c-FLIPL Lys48/Lys63 branched polyubiquitination and proteasomal degradation. Histone deacetylase (HDAC) inhibition induced Ku70 and c-FLIPL acetylation, leading to release of c-FLIPL and Bax from Ku70, increased Ku70 and c-FLIPL Lys48/Lys63 branched polyubiquitination via the ITCH-UBE4B complex, and induction of apoptosis. UBE4B depletion in our neuroblastoma cell lines model led to reduced polyubiquitination and increased levels of Ku70 and c-FLIPL proteins leading to the massive reduction of apoptosis induced by HDAC inhibition via stabilization of Ku70 and c-FLIPL proteins allowing the inhibition of the full caspase 8 activation. Our results have identified novel interactions and novel targets for UBE4B ubiquitin ligase activity and a direct role of the ITCH-UBE4B complex in responses of neuroblastoma cells to HDAC inhibition, suggesting that the ITCH-UBE4B complex plays a critical role in responses of neuroblastoma to therapy and suggesting a potential mechanism underlying the association of UBE4B expression with neuroblastoma patient outcomes. Citation Format: Christophe Le Clorennec, Divya Subramonian, Yuchen Huo, Peter E. Zage. UBE4B interacts with the ITCH E3 ubiquitin ligase to induce Ku70 and c-FLIPL K63/K48 branched polyubiquitination and enhanced neuroblastoma HDACi-mediated apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3702.
Abstract 3941: TNG908 is an MTAPnull-selective PRMT5 inhibitor that drives tumor regressions in <i>MTAP</i>-deleted xenograft models across multiple histologies
Authors: Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Erik W. Wilker, Lina Gu, Charles B. Davis, Minjie Zhang, Doug Whittington, Deepali Gotur, Matthew J. Goldstein, Heather DiBenedetto, Marc S. Rudoltz, Alan Huang, John P. Maxwell
Journal: Cancer Research (2022)

Abstract TNG908 is an investigational PRMT5 inhibitor with a novel MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10-15% of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. TNG908 selectively binds the PRMT5-MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, which is postulated to create a large therapeutic index relative to PRMT5 inhibitors currently in clinical development. TNG908 is 15X selective for MTAPnull cell lines over isogenic MTAPWT cell lines, and has marked selectivity for MTAP-deleted cancer cell lines independent of lineage in a large, diverse cell line panel. In vitro mechanistic studies confirm that MTAPnull-selective PRMT5 inhibitors can selectively target MTAPnull cancer cells in either an admixture of MTAPnull and MTAPWT cells, or with intracellular MTA accumulation 2-5X relative to basal levels in MTAPWT cells. Oral administration of TNG908 drives dose-dependent, MTAPnull-selective antitumor activity in multiple xenograft models, including tumor regressions in models representing non-small cell lung cancer (adenocarcinoma and squamous), cholangiocarcinoma, urothelial carcinoma, and others. Preclinical studies suggest clinical combinations that leverage PRMT5 biology and/or concurrent oncogenic driver mutations, such as KRASG12C. In summary, TNG908 is a novel, potent PRMT5 inhibitor with excellent drug-like properties and strong preclinical activity in multiple xenograft models that has the potential for histology-agnostic clinical development in MTAP-deleted solid tumors. Citation Format: Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Erik W. Wilker, Lina Gu, Charles B. Davis, Minjie Zhang, Doug Whittington, Deepali Gotur, Matthew J. Goldstein, Heather DiBenedetto, Marc S. Rudoltz, Alan Huang, John P. Maxwell. TNG908 is an MTAPnull-selective PRMT5 inhibitor that drives tumor regressions in MTAP-deleted xenograft models across multiple histologies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3941.
Abstract 1506: <i>APOBEC3A a</i> causative agent in cancer-related chromosomal instability and STING driven metastasis
Authors: Sonja Maria Woermann, Amy Zhang, Fredrik I. Thege, Chris Gates, Reuben S. Harris, Susan R. Ross, Faiyaz Notta, Anirban Maitra, Andrew D. Rhim
Journal: Cancer Research (2022)

Abstract Chromosomal instability (CIN), a hallmark of cancer, has been associated with a highly metastatic phenotype in numerous cancers. Mechanisms by which these genomic events occur during the lifespan of a neoplasm have yet to be fully delineated. In our study we identified a novel function for APOBEC3A (A3A), a primate-specific cytidine deaminase upregulated in multiple cancers including Pancreatic ductal adenocarcinoma (PDAC), in the initiation of CIN.We demonstrate that A3A is not routinely detected in non-diseased pancreata; however, expression was detected in the epithelial and stromal compartments from patients with chronic pancreatitis and in precursor lesions of PDAC and is further significantly increased in invasive neoplasia. Strikingly, we found that A3A expression but not A3A-induced mutagenesis, was associated with a significantly reduced overall survival in PDAC. By employing a variety of genetic tools, we identified a novel function for A3A in initiating CIN, underscoring its potential role in driving the observed early metastatic propensity in PDAC. Using a series of in vivo and in vitro models, we demonstrate that A3A-induced CIN leads to aggressive cancer, featuring enhanced, STING-dependent, distant organ seeding and metastatic growth. As a consequence of aberrant A3A function and CIN-mediated upregulation of STING, NfkB and Stat3 pathways were activated. More importantly, all these effects were independent of the deaminase domain, underscoring a novel role of A3A beyond its established canonical function. Remarkably, in a novel autochthonous murine model of PDA expressing human A3A, we identified numerous copy number changes, homologous to those altered in A3A overexpressing patient tumors, including deletions in DNA repair pathway genes. While we showed that A3A-expressing PDAC cells do not fully phenocopy a BRCA mutation-like phenotype, A3A-expressing PDAC cells are exceptionally sensitive to PARP inhibition and DNA cross linking agents, recapitulating a state of “chemical BRCAness”. The combined effect of deletions in these genes has yet to be ascertained, and we hypothesize that these losses further add to ongoing DNA damage overall in PDAC. In summary, our study shows, that A3A drives metastasis and specific deletions through a deaminase-independent initiation of CIN, with potential implications for targeted treatment strategies in pancreatic cancer. Citation Format: Sonja Maria Woermann, Amy Zhang, Fredrik I. Thege, Chris Gates, Reuben S. Harris, Susan R. Ross, Faiyaz Notta, Anirban Maitra, Andrew D. Rhim. APOBEC3A a causative agent in cancer-related chromosomal instability and STING driven metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1506.
Analysis of a Trend Reversal in US Lumpectomy Rates From 2005 Through 2017 Using 3 Nationwide Data Sets
Authors: Jonas A. Nelson, Robyn N. Rubenstein, Kathryn Haglich, Jacqueline J. Chu, Shen Yin, Carrie S. Stern, Monica Morrow, Babak J. Mehrara, Mary L. Gemignani, Evan Matros
Journal: JAMA Surgery (2022)

Rates of lumpectomy for breast cancer management in the United States previously declined in favor of more aggressive surgical options, such as mastectomy and contralateral prophylactic mastectomy (CPM).To evaluate longitudinal trends in the rates of lumpectomy and mastectomy, including unilateral mastectomy vs CPM rates, and to determine characteristics associated with current surgical practice using 3 national data sets.Data from the National Surgical Quality Improvement Program (NSQIP), Surveillance, Epidemiology, and End Results (SEER) program, and National Cancer Database (NCDB) were examined to evaluate trends in lumpectomy and mastectomy rates from 2005 through 2017. Mastectomy rates were also evaluated with a focus on CPM. Longitudinal trends were analyzed using the Cochran-Armitage test for trend. Multivariate logistic regression models were performed on the NCDB data set to identify predictors of lumpectomy and CPM.A study sample of 3 467 645 female surgical breast cancer patients was analyzed. Lumpectomy rates reached a nadir between 2010 and 2013, with a significant increase thereafter. Conversely, in comparison with lumpectomy rates, overall mastectomy rates declined significantly starting in 2013. Cochran-Armitage trend tests demonstrated an annual decrease in lumpectomy rates of 1.31% (95% CI, 1.30%-1.32%), 0.07% (95% CI, 0.01%-0.12%), and 0.15% (95% CI, 0.15%-0.16%) for NSQIP, SEER, and NCDB, respectively, from 2005 to 2013 (P < .001, P = .01, and P < .001, respectively). From 2013 to 2017, the annual increase in lumpectomy rates was 0.96% (95% CI, 0.95%-0.98%), 1.60% (95% CI, 1.59%-1.62%), and 1.66% (95% CI, 1.65%-1.67%) for NSQIP, SEER, and NCDB, respectively (all P < .001). Comparisons of specific mastectomy types showed that unilateral mastectomy and CPM rates stabilized after 2013, with unilateral mastectomy rates remaining higher than CPM rates throughout the entire time period.This observational longitudinal analysis indicated a trend reversal with an increase in lumpectomy rates since 2013 and an associated decline in mastectomies. The steady increase in CPM rates from 2005 to 2013 has since stabilized. The reasons for the recent reversal in trends are likely multifactorial. Further qualitative and quantitative research is required to understand the factors driving these recent practice changes and their associations with patient-reported outcomes.
Abstract 883: Defining the observed mutual exclusivity between <i>SF3B1</i> and <i>TP53</i> mutations in cancer
Authors: Riley Bergman, Ben Park, Sarah Croessmann
Journal: Cancer Research (2022)

Abstract SF3B1 is the most commonly mutated splicing factor in cancer, occurring in a broad variety of hematologic and solid malignancies, including: breast, melanoma, pancreatic, bladder, colorectal, leukemia, and more. SF3B1 is a protein component of the spliceosome responsible for recognizing intronic splice sites and stabilizing the interaction between the spliceosome and pre-mRNA transcripts. Hotspot mutations in SF3B1 result in a neomorphic protein that causes aberrant splicing of hundreds of transcripts. These transcriptional alterations have several proposed impacts on known cancer pathways; however, the mechanisms by which SF3B1 mutations contribute to tumorigenesis are incompletely understood. Interestingly, systematic analysis of online cancer databases shows SF3B1 mutations and TP53 alterations are mutually exclusive in cancers with predominant SF3B1 hotspots, suggesting either synthetic lethality or overlapping roles in promoting tumorigenesis. To address this question, TP53 was knocked-out using CRISPR-Cas9 in AAV-generated SF3B1 K700E mutant knock-in and wild type MCF-10A breast epithelial cells. Successful generation of TP53 knock-outs in both the SF3B1 mutant and wild type groups suggests the mutations are unlikely to be synthetic lethal. Instead, this finding may direct us to novel mechanisms by which SF3B1 mutations contribute to cancer development and progression. Two overarching areas of interest based on preliminary data include changes in mitochondrial metabolism and metabolic reprogramming and alterations in DNA damage, repair, and genomic stability. Further defining the relationship between mutant SF3B1 and TP53 may reveal new mechanisms of tumorigenesis and reveal therapeutic vulnerabilities that can be additionally leveraged against the large subset of cancers with TP53 mutations. Citation Format: Riley Bergman, Ben Park, Sarah Croessmann. Defining the observed mutual exclusivity between SF3B1 and TP53 mutations in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 883.
Abstract LB177: Widespread hypertranscription in aggressive human cancer
Authors: Matthew Zatzman, Fabio Fuligni, Ryan Ripsman, Tannu Suwal, Lisa-Monique Edward, Rob Denroche, Gun Ho Jang, Faiyaz Notta, Steven Gallinger, Saravana P. Selvanathan, Jeffrey Toretsky, Matthew D. Hellmann, Uri Tabori, Annie Huang, Adam Shlien
Journal: Cancer Research (2022)

Abstract Cancers are often defined by the dysregulation of specific transcriptional programs; however, the importance of global transcriptional changes is less understood. Hypertranscription is the genome-wide increase in RNA output. Hypertranscription’s prevalence, underlying drivers and prognostic significance are undefined in primary human cancer. This is due in part to limitations of expression profiling methods, which assume equal RNA output between samples. Here, we developed a computational method to directly measure hypertranscription in 7,494 human tumors, spanning 31 cancer types. Hypertranscription is ubiquitous across cancer, especially in aggressive disease. It defines patient subgroups with worse survival, even within well-established subtypes. Our data suggest that loss of transcriptional suppression underpins the hypertranscriptional phenotype. Single-cell analysis reveals hypertranscriptional clones, which dominate transcript production regardless of their size. Finally, patients with hypertranscribed mutations have improved response to immune checkpoint therapy. Our results provide fundamental insights into gene dysregulation across human cancers and may prove useful in identifying patients that would benefit from novel therapies. Citation Format: Matthew Zatzman, Fabio Fuligni, Ryan Ripsman, Tannu Suwal, Lisa-Monique Edward, Rob Denroche, Gun Ho Jang, Faiyaz Notta, Steven Gallinger, Saravana P. Selvanathan, Jeffrey Toretsky, Matthew D. Hellmann, Uri Tabori, Annie Huang, Adam Shlien. Widespread hypertranscription in aggressive human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB177.
Abstract 3054: Pan-cancer characterization of the tumor mycobiome and its clinical effects
Authors: Lian Narunsky Haziza, Gregory D. Sepich-Poore, Ilana Livyatan, Omer Asraf, Cameron Martino, Deborah Nejman, Nancy Gavert, Jason E. Stajich, Guy Amit, Antonio González, Stephen Wandro, Gili Perry, Ruthie Ariel, Arnon Meltser, Justin P. Shaffer, Qiyun Zhu, Nora Balint-Lahat, Iris Barshack, Maya Dadian, Einav N. Gal-Yam, Sandip P. Pate, Amir Bashan, Austin D. Swafford, Yitzhak Pilpel, Rob Knight, Ravid Straussman
Journal: Cancer Research (2022)

Abstract While the study of the tumor microbiome and its effects on cancer biology has expanded considerably over the last few years, most of this research focused on bacteria and viruses, leaving behind the fungal kingdom. Recently, a few studies have demonstrated that specific fungi may promote tumor progression, stressing the importance of comprehensively studying the tumor mycobiome and its effects. To address this, we have characterized the mycobiome in 1,183 human tumors and their adjacent tissues, originating from eight major solid tumor types. Staining and imaging demonstrated the presence of fungi in both cancer and immune cells, with tumor-type specific distribution patterns. Quantitative PCR of the fungal 5.8s rDNA revealed the presence of fungal DNA in all tumor types. To characterize the tumor mycobiome and address potential contamination during tissue handling and processing, we subjected all samples, as well as 295 negative controls of different types, to sequencing of the ITS2 region that is situated between fungal rRNA genes. We found cancer-type specific mycobial signatures with relatively high similarity between tumors and their adjacent tissues. While the fungal mycobiome had a lower species richness as compared to the bacterial microbiome of the same tumors, fungi showed significant co-occurrences with specific bacteria, suggesting the existence of ecological niches within the tumors. We also found significant correlations with clinical parameters such as patient’s age, tumor stage, progression-free survival, overall survival, and response to immune checkpoint blockade therapy. Characterization of the tumor mycobiome may add a biologically relevant, previously overlooked, component to be considered in the study of cancer, including its effects on tumor initiation, progression, diagnosis, and response to therapy. Citation Format: Lian Narunsky Haziza, Gregory D. Sepich-Poore, Ilana Livyatan, Omer Asraf, Cameron Martino, Deborah Nejman, Nancy Gavert, Jason E. Stajich, Guy Amit, Antonio González, Stephen Wandro, Gili Perry, Ruthie Ariel, Arnon Meltser, Justin P. Shaffer, Qiyun Zhu, Nora Balint-Lahat, Iris Barshack, Maya Dadian, Einav N. Gal-Yam, Sandip P. Pate, Amir Bashan, Austin D. Swafford, Yitzhak Pilpel, Rob Knight, Ravid Straussman. Pan-cancer characterization of the tumor mycobiome and its clinical effects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3054.
Abstract 5618: Multi-armed myxoma virus has therapeutic potential for treatment of multiple myeloma
Authors: Ana L. de Matos, Rachel Dutcher, Lina S. Franco, Lino E. Torres-Dominguez, Heather Hrach, Mario Abrantes, Wazir Abdullahi, Zachary Tacner, Dillon McCrite, Nicole Grigiatis, Jack St. Peter, Leslie L. Sharp
Journal: Cancer Research (2022)

Abstract Oncolytic viruses (OV) selectively replicate in and lyse tumor cells and provide stimulation to the immune system, representing a promising therapeutic option in development to treat cancers that do not respond well to treatment with immune checkpoint inhibitors. Myxoma virus (MYXV) is a member of the Pox family of double stranded DNA viruses and infects cancer cell lines of humans and other species. The genome of MYXV is relatively large and is amenable to engineering for expression of transgenic proteins, making it an excellent oncolytic virus for introduction of immunomodulatory proteins. We generated MYXV carrying IL-12 and decorin. IL-12 is an immune modulator that activates T- and NK-cells. Cellular responses to decorin include tumor cell intrinsic signaling effects, tumor matrix modulation, and inhibition of the TGF-beta pathway. We demonstrate the activity of multi-armed MYXV against human and mouse multiple myeloma (MM) cancer cell lines. Efficacy and mechanism of action of multi-armed myxoma virus was also demonstrated in vivo via syngeneic and xenograft models. Multi-armed MYXV represents a promising therapeutic option for MM patients that do not respond well to immunotherapy. Citation Format: Ana L. de Matos, Rachel Dutcher, Lina S. Franco, Lino E. Torres-Dominguez, Heather Hrach, Mario Abrantes, Wazir Abdullahi, Zachary Tacner, Dillon McCrite, Nicole Grigiatis, Jack St. Peter, Leslie L. Sharp. Multi-armed myxoma virus has therapeutic potential for treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5618.
Abstract 3340: Small molecule mediated stabilization of PP2A modulates the homologous recombination pathway and potentiates DNA damage-induced cell death
Authors: Rita A. Avelar, Amy Armstrong, Goutham Narla, Analisa DiFeo
Journal: Cancer Research (2022)

Abstract High Grade Serous Carcinoma (HGSC) is the most lethal ovarian cancer subtype and accounts for approximately 60% of all ovarian tumors. Despite recent advances in drug development and increased understanding of genetic alterations that drive HGSC progression, mortality has not declined, highlighting the need for novel therapies. PARP inhibitors (PARPi) have become the mainstay of HGSC targeted therapy research given that these tumors are driven by a high degree of genomic instability resulting from the combination of fast DNA replication rates and numerous defects in the DNA-damage response (DDR) pathway. Nonetheless, only ~25% of these patients initially respond to treatment and a significant percentage eventually relapses with resistant disease. Here, we discovered that a Small Molecule Activator of Protein Phosphatase 2A (PP2A) (SMAP-061) induces apoptosis in both established and patient-derived HGSC cell lines as well as in genetically distinct Patient-Derived Xenograft (PDX) mouse models. Interestingly, we also uncovered that several genes that make-up the heterotrimer PP2A tumor suppressor protein are heterozygously lost in more than 95% of HGSC tumors, second only to p53. Mechanistically, we show that stabilization of PP2A protein by SMAP-061 inhibits the Homologous Recombination (HR) pathway via the direct inhibition of RAD51, ultimately leading to chronic accumulation of DNA damage and thus programmed cell death. Furthermore, we found that SMAP-061’s ability to inhibit HR potentiated the effects of PARP inhibition and resulted in synergistic cell death in both HR proficient and deficient models. These studies emphasize the potential of PP2A activators to expand the patient population that can benefit from PARPi therapies and possibly overcome PARPi resistance. In sum, our data highlights a new role of PP2A in regulating the DDR pathway in HGSC and supports the use of SMAPs in both HR proficient and deficient HGSC tumors. Citation Format: Rita A. Avelar, Amy Armstrong, Goutham Narla, Analisa DiFeo. Small molecule mediated stabilization of PP2A modulates the homologous recombination pathway and potentiates DNA damage-induced cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3340.
Risk factors for prolonged time to hospital discharge after ambulatory cholecystectomy under general anaesthesia. A retrospective cohort study
Authors: Lucile Picard, Baptiste Duceau, Amélie Cambriel, Thibault Voron, Sarah Makoudi, Amy S Tsai, Lassaad Yazid, Anne Soulier, Charles Paugam, Thomas Lescot, Francis Bonnet, Franck Verdonk
Journal: International Journal of Surgery (2022)